Evidence that Increased Circulating 1α,25-Dihydroxyvitamin D is the Probable Cause for Abnormal Calcium Metabolism in Sarcoidosis

Abstract

A B S T R A C T Mean plasma 1,,25-dihydroxyvitamin D [1,,25(OH)2D] was significantly increased and serum parathyroid hormone was suppressed in three patients with sarcoidosis and hypercalcemia. Prednisone lowered the mean plasma 1,,25(OH)2D to normal range and corrected the hypercalcemia. To elucidate the mechanism for the increased sensitivity to vitamin D in this disorder, the effects of orally-administered vitamin D2 were determined in seven normal subjects, four patients with sarcoidosis and normal calcium metabolism and three patients with sarcoidosis and a history of hypercalcemia who were normocalcemic when studied. Serum and urinary calcium, serum 25-hydroxyvitamin D (25-OHD), plasma 1a,,25(OH)2D and, in some studies, calcium balance were measured. Vitamin D2, 250 ,ug a day for 12 d, produced little, ifany, change in mean plasma 1a,25(OH)2D and in urinary calcium in the normals and in the patients with normal calcium metabolism. In contrast, vitamin D2 produced increases in plasma 10,,25(OH)2D from concentrations which were within the normal range (20-55 pg/ml) to abnormal values and increased urinary calcium in two patients with abnormal calcium metabolism. In an abbreviated study in the third patient, vitamin D2, 250 ,ug a day for 4 d, also increased plasma 1,,25(OH)2D abnormally from a normal value. There was a highly significant correlation between plasma 1,,25(OH)2D and urinary calcium. Serum 25-OHD and serum calcium remained within the normal range in all subjects and patients. These findings provide evidence that the defect in calcium metabolism in sarcoidosis probably results from impaired regulation of the production and(or) degrada-

Hypercalcemia and soft tissue calcification owing to sarcoidosis: The sunlight-cola connection

“…(7) Fuller Albright published elegant calcium balance studies in 1956 showing a pattern of hypercalcemia and hypercalciuria in sarcoid patients that was consistent with excess vitamin D. (8) Later, in the 1970s, it was shown that 1,25(OH) 2 D levels were elevated in hypercalcemic patients with sarcoidosis. (9,10) However, the source of this 1,25(OH) 2 D was not immediately clear. In 1981, Barbour and colleagues described a patient with renal failure, sarcoidosis-related hypercalcemia, and elevated serum 1,25(OH) 2 D. When the patient underwent bilateral nephrectomy in anticipation of a kidney transplant, his 1,25(OH) 2 D level remained elevated, and he continued to require steroids to maintain the serum calcium level within the normal range.…”

Sarcoidosis Initially Manifesting as Symptomatic Hypercalcemia with the Absence of Organic Involvement.

“…Extrarenal production of 1,25(OH)2Dis the main mechanism for development of hypercalcemia in sarcoidosis (6,7). In certain granulomatousdiseases such as sarcoidosis, various cytokines are knownto induce 25(OH)D-loc-hydroxylase in macrophages, in which serum ACE,a marker for macrophage activation, is often elevated (8,9). Therefore, hypercalcemic sarcoid patients show abnormally high 1,25(OH)2D levels in spite of having undetectable levels of intact PTH (7).…”

Prognostic Factors in Sarcoidosis

“…25-hydroxyvitamin D undergoes 1α-hydroxylation to form more active 1,25 dihydroxyvitamin D, and granuloma cells possess high amounts of 25-hydroxyvitamin D-1α-hydroxylase, responsible for this conversion (Bell et al, 1979). Elevated serum calcium concentrations may be found in about 11% of patients with sarcoidosis, abnormal urinary calcium loss in about 40 % of patients, and nephrocalcinosis in about 10 % [Ianuzzi et al, 2007].…”